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BMC Med Genomics. 2018 Feb 13;11(Suppl 1):12. doi: 10.1186/s12920-018-0330-5.

Computational master-regulator search reveals mTOR and PI3K pathways responsible for low sensitivity of NCI-H292 and A427 lung cancer cell lines to cytotoxic action of p53 activator Nutlin-3.

Author information

1
Institute of Chemical Biology and Fundamental Medicine, SBRAN, Novosibirsk, Russia.
2
Biosoft.ru, Ltd, Novosibirsk, Russia.
3
geneXplain GmbH, D-38302, Wolfenbüttel, Germany.
4
Institute of Chemical Biology and Fundamental Medicine, SBRAN, Novosibirsk, Russia. alexander.kel@genexplain.com.
5
Biosoft.ru, Ltd, Novosibirsk, Russia. alexander.kel@genexplain.com.
6
geneXplain GmbH, D-38302, Wolfenbüttel, Germany. alexander.kel@genexplain.com.

Abstract

BACKGROUND:

Small molecule Nutlin-3 reactivates p53 in cancer cells by interacting with the complex between p53 and its repressor Mdm-2 and causing an increase in cancer cell apoptosis. Therefore, Nutlin-3 has potent anticancer properties. Clinical and experimental studies of Nutlin-3 showed that some cancer cells may lose sensitivity to this compound. Here we analyze possible mechanisms for insensitivity of cancer cells to Nutlin-3.

METHODS:

We applied upstream analysis approach implemented in geneXplain platform ( genexplain.com ) using TRANSFAC® database of transcription factors and their binding sites in genome and using TRANSPATH® database of signal transduction network with associated software such as Match™ and Composite Module Analyst (CMA).

RESULTS:

Using genome-wide gene expression profiling we compared several lung cancer cell lines and showed that expression programs executed in Nutlin-3 insensitive cell lines significantly differ from that of Nutlin-3 sensitive cell lines. Using artificial intelligence approach embed in CMA software, we identified a set of transcription factors cooperatively binding to the promoters of genes up-regulated in the Nutlin-3 insensitive cell lines. Graph analysis of signal transduction network upstream of these transcription factors allowed us to identify potential master-regulators responsible for maintaining such low sensitivity to Nutlin-3 with the most promising candidate mTOR, which acts in the context of activated PI3K pathway. These finding were validated experimentally using an array of chemical inhibitors.

CONCLUSIONS:

We showed that the Nutlin-3 insensitive cell lines are actually highly sensitive to the dual PI3K/mTOR inhibitor NVP-BEZ235, while no responding to either PI3K -specific LY294002 nor Bcl-XL specific 2,3-DCPE compounds.

KEYWORDS:

Lung cancer cell lines; Nutlin-3; Sensitivity to anticancer drugs; TRANSFAC; Transcription factors; p53

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